Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Doris A. Stoffers

Abstract

LIM-domain-binding protein 1 (Ldb1) and the LIM-Homeodomain factor (LIM-HD) Islet-1 (Isl-1) share a robust functional relationship in directing differentiation of developmental progenitor populations. However, their mechanistic role in terminally differentiated cells is uncharacterized. In the developing endocrine pancreas, conditional ablation of either Isl-1 in the pancreatic epithelium or Ldb1 in the Pax6+ pancreatic endocrine progenitors suspended pancreatic endocrine differentiation. In light of their functional requirement in the developing endocrine pancreas, both factors remain ubiquitously enriched in the distinct, terminally differentiated endocrine cell-types that comprise the adult endocrine pancreas. To determine the requirement for Ldb1 and Isl-1 in the mature pancreatic β-cell, I combined physiological characterization of inducible, β-cell-specific loss-of-function mice with high-throughput cistromic and transcriptomic analyses. Ldb1 and Isl-1 were required for maintaining the glucose homeostatic role of the mature β-cell as well as the terminally differentiated status of the β-cell. Consistent with the established mechanistic relationship between Ldb1 and Isl-1 in progenitor populations, Ldb1 and Isl-1 were co-enriched throughout the β-cell genome. Comparison of our islet- and insulinoma-based cistromic data sets with the glucagonoma Isl-1 cistrome revealed differential enrichment of Isl-1 between the immortalized murine α- and β-cell lines; this differential enrichment may underlie the distinct terminal identities of α- and β-cells. Contextualized through the broader role of Ldb1-mediated complexes in directing cell fate decisions, my findings in the mature β-cell indicate that Ldb1-mediated complexes are likely responsible for directing and maintaining the terminal differentiation status of all pancreatic endocrine cell types.

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